This application describes a systematic 5-year training plan and experimental studies that will lead to an independent career in translational neuroscience with a focus on the effects of stimulants such as cocaine on the brain. Quantitative optical fluorescence and spectroscopic imaging combined with high-resolution magnetic resonance imaging (9.4T) will be used in the planned research. In previous work, the candidate has developed a catheter-based optical diffusion and fluorescence (ODF) instrument, which has been validated for simultaneously detecting changes in cerebral blood volume (CBV), tissue oxygenation (StO2) and intracellular calcium [Ca++]i) during ischemia (Du et al. J Cereb Blood Flow Metab., 2005(25), 1078- 1092). Preliminary results with this system have been obtained in which cocaine-naive rats, and rats with a history of self-administration of cocaine, are compared after an acute cocaine challenge. In drug-naive rats cocaine induced a mild, transient decrease in CBV and StO2 and a gradual 10% increase in [Ca++]i. In chronically cocaine exposed rats, cocaine produced a rapid >20% increase in [Ca++]i and significant, persistent decreases in CBV and StO2. Furthermore in drug naive rats have cocaine-induced increases in [Ca++]i occur independent of its actions on CBV and StO2. Cocaine-induced excessive [Ca++]i increases (as observed in rats self-administering cocaine) would make cells more vulnerable to injury particularly when simultaneously coupled with decreases in CBV and StO2 (Du et a/., submitted to J. Neuroscience, 2006). Here we propose a strategy to separate out direct effects of cocaine on the vasculature from direct effects on cortical function. Specific aims are: (1) characterization of the effects of acute cocaine on hemodynamics and calcium transients; (2) measurement of cocaine's effect on the MRI apparent diffusion coefficient to determine if there is cellular damage and fMRI measurements of effects of forepaw stimulation in cocaine self-administering and cocaine-naive rats to determine if there are effects on cortical functioning, (3) evaluation of the effects of abstinence from cocaine on self-administering animals as a model for the physiological changes that occur during drug withdrawal, and (4) making technical improvements on the ODF system to reduce the size of the optical probe (currently 3mm) to 300[unreadable]m. This fourth aim should permit measurements of neural signals from deeper brain regions in future studies. The PI is seeking this K25 award to further extend her knowledge of the physiology, biochemistry and pharmacology underlying the brain's responses to acute and chronic administration of abused drugs. [unreadable] [unreadable] [unreadable]